KR100520857B1 - Methods and apparatus for multi-spectrum analysis in noninvasive infrared spectroscopy - Google Patents

Abstract

A method and apparatus are disclosed for determining the concentration of analyte present in a sample using multispectral analysis in the near and mid infrared range. Incident radiation comprising a plurality of individual, non-overlapping regions of wavelengths in the range of approximately 1100 to 5000 nm is used to scan the sample. Diffusely reflected radiation from the sample is detected and a value indicative of the concentration of the analyte is obtained using the application of chemical metric techniques. Information obtained from each non-overlapping region of wavelengths can be cross-correlated to remove background interference.

Description

Methods and apparatus for multi-spectrum analysis in noninvasive infrared spectroscopy

The present invention is a method and apparatus for measuring the concentration of a target analyte in a sample using multi-spectral analysis. The present invention can be applied to a wide range of chemical assays, and specifically to noninvasive infrared spectroscopy of blood analytes.

Measurement of the concentration of various blood components can be applied in various procedures for the diagnosis and treatment of body abnormalities and diseases. One important application is the measurement of blood sugar. In particular, patients suffering from diabetes should be regularly checked for blood glucose levels, and for insulin-dependent or type I diabetes, it is often necessary or desirable to have blood glucose tests several times a day. In addition, measurement of blood cholesterol levels provides important information for the treatment or prevention of coronary artery disease, and measurement of other organic blood analytes such as bilirubin and alcohol is also important in a variety of diagnostic environments.

The most accurate and widespread practical method of obtaining blood analyte concentrations includes the extraction of blood from patients, which can be used in laboratories using high accuracy and sensitive analytical evaluation techniques or by using less accurate self test methods. Is analyzed. In particular, traditional blood glucose monitoring methods take a blood sample (eg, by incision at the fingertip) for each test and use a glucose meter (spectrophotometer to read the clocos concentration) or a color calibration method using a glucos level. Requires diabetics to read. This invasive blood extraction poses pain and burdensome burden to diabetics and exposes diabetics to infection, especially at the light of essential test frequencies. For this reason, the surveillance process may be rejected by diabetics.

Accordingly, it is recognized that simple and accurate methods and apparatus for non-invasive measurement of blood analyte concentrations are desired in the art, particularly in the blood glucose monitoring environment of diabetics. One way to approach this problem is to use the traditional method of near-infrared (near-IR or "NIR") analysis, extracting analyte characteristic information from a sample provided with the measurement of absorbance of one or more specific wavelengths. It is used to

The near infrared absorbance spectrum of a liquid sample contains a lot of information about the various organic components of the sample. In particular, vibration, rotation, and stretching energy associated with organic molecular structures (carbon-carbon, carbon-hydrogen, carbon-nitrogen, and nitrogen-hydrogen chemical bonds) are detected for concentrations of various organic components present in the sample. Create perturbations in the near-infrared region that can be associated and related. However, in complex sample matrices, the near-infrared spectrum is also partially due to the similarity of the structures between the analytes, the relative levels of the analyte concentrations, the interference relations between the analytes, and the inherent electronic and chemical "noise" in certain systems. Includes a significant amount of interference. This interference reduces the efficiency and accuracy of the measurements obtained using near infrared spectroscopy to measure the concentration of the liquid sample analyte. However, many near infrared devices and methods have been disclosed for providing noninvasive blood analyte measurements.

U.S. by Purdy et al. Patent 5,360,004 discloses a method and apparatus for measuring the concentration of blood analytes, wherein a part of the human body is irradiated with radiation comprising continuous wavelength incident radiation of two or more separate bands. Purdy et al. Emphasize a filtering technique that specifically blocks radiation at two peaks of the NIR absorption spectrum for moisture occurring at about 1440 and 1935 nm. This selective blocking is performed to avoid the heating effect that can occur with absorption of radiation by moisture when a part of the human body is irradiated.

In contrast, Yang et al., U.S. Patent 5,267,152 discloses a non-invasive device and technology for measuring blood glucose concentration using only the IR spectral portion comprising an NIR water absorption peak (eg, a “water transmission window.”) Optical The controlled light is directed to a tissue source and then collected by an integrating sphere, which is then analyzed and stored to calculate blood glucose levels using a stored reference calibration curve.

Also disclosed is a device for use in the measurement of analyte concentrations in complex samples.

See, eg, U.S. by Richardson et al. Patent 5,242,602 discloses a method for analyzing aqueous systems to detect multiple active or inert moisture treatment components. The method uses chemometrics algorithms to extract segments of spectral data obtained to measure absorbance or emission spectra of components over a range of 200 to 2500 nm, and to measure the amount of multiple performance indicators. Includes the application of.

U.S. by Nygaard et al. Patent 5,252,829 discloses a method and apparatus for measuring urea concentration in a milk sample using infrared attenuation measurement techniques. Multivariate techniques are performed to measure the spectral contribution of known components using partial least squares algorithms, principal component regression, multiple linear regression, or artificial neural network knowledge. Calibration is performed by calculating the component contribution to blocking the analyte signal of interest. Therefore, Nygaard et al. Describe the technique of multiple analyte infrared attenuation and compensation for the effects of background analytes to obtain more accurate measurements.

U.S. by Ross et al. Patent 4,306,152 discloses an optical fluid analyzer designed to minimize the measurement accuracy of a turbid sample or the effect of background absorption (i.e. total or base level light absorption of a fluid) that is difficult to analyze. The device measures another signal of the selected wavelength for characteristic light absorption and approximate background absorption of the sample component of interest, and then subtracts to reduce the background component of the analyte dependent signal.

The accuracy of the information obtained using the methods and apparatus described above is limited by the spectral interference generated by the analyte having an absorption spectrum in the background, i.e., the near infrared range. Significant background noise represents inherent system limitations, especially when the analyte is very small. In view of these limitations, for example, by avoiding water absorption peaks that make use of increased radiation intensity, or by reducing the amount of spectral information to be analyzed, or by subtracting or compensating techniques based on an approximation of background absorption. Attempts have been made to improve the signal-to-noise ratio. While these techniques have made some improvements, there remains a need for providing methods and devices that can enable more accurate measurement of analyte concentrations in liquid matrices, particularly in the context of blood glucose monitoring.

<Summary of invention>

Accordingly, it is a primary object of the present invention to meet the aforementioned needs by providing a method for measuring the concentration of an analyte present in a sample having various background matrices and possibly possibly substantial component interference. The method accounts for the similarity of structures among the various components present in the sample, the relative magnitude of the analyte concentration, and the causes of spectral interference due to various sample components and means change.

The method generally comprises: (1) identifying several individual, non-overlapping regions of wavelength in the near infrared that have a high correlation with the concentration of the analyte; (2) irradiating a sample with incident radiation comprising the regions to obtain spectral attenuated radiation as a result of the interaction of sample components; (3) detecting the spectral attenuated radiation; (4) measuring the intensity of the spectral attenuated radiation at the wavelength within the non-overlapping regions of the wavelength; And (5) correlating the measurements to obtain a value representative of the concentration of the analyte.

According to one aspect of the invention, a method is provided wherein spectral data from both near and mid-infrared regions is analyzed to obtain analyte characterization information. Therefore, the method is generally associated with the concentration of the selected analyte or provides several individual information in the near-infrared and mid-infrared regions, typically in the range of approximately 1100-5000 nm, which provides information on measurement and instrumentation parameters. The identification of the wavelength of the non-overlapping regions.

According to another feature of the invention, generally, (1) selecting several individual, non-overlapping regions of wavelength within the near infrared range with high correlation to the concentration of an analyte; (2) irradiating the sample using infrared light comprising a spectral range selected to obtain spectral altered radiation; (3) optically filtering the spectrally altered radiation to isolate or highlight a portion of radiation from each non-overlapped region; (4) collecting and measuring the intensity of the optically filtered radiation using a detector; And obtaining a value representative of the analyte concentration by using the defined mathematical model in optically filtered radiation.

It is also an object of the present invention to provide a spectroscopic measuring device for measuring the concentration of analyte present in a sample having a variable background matrix and substantial component interference. The apparatus includes an array of detectors capable of collecting and measuring attenuated radiation reflected from a sample. The apparatus is used in multispectral analysis to obtain spectral information including not only signals related to instrument background noise and interference spectral information, but also analyte characteristic signals. Chamometric techniques are used to construct a filter element that can improve the correlation between analyte characterization information and the analyte concentration and to derive a system algorithm for determining analyte concentration values. In one aspect of the invention, a diffraction grating system is used to obtain analyte characteristic spectral information detected by a linear detector array capable of analyzing up to several hundred data points or wavelengths simultaneously.

1 is a schematic diagram of a device with a linear array of detectors capable of analyzing wavelengths in both near and mid-infrared regions constructed in accordance with the present invention.

2 is a schematic diagram of another example device constructed in accordance with the present invention;

3 is a graph depicting time dependent scans taken during a vivo glucose tolerance study.

4 is a graph depicting the results obtained from non-invasive measurements of blood glucose levels treated using the method of the present invention.

Modes for Carrying Out the Invention

Before describing the invention in detail, it is to be understood that the invention is not limited to the specific components described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural objects unless the context otherwise specifies. Thus, for example, reference to "an analyte" includes a mixture of analytes, reference to "an optical transfer cell" includes two or more light transmission cells, and the term "a means for reflectively transmitting radiation". Reference includes two or more such means, reference to “a wavelength” includes two or more wavelengths, “a chemometrics algorithm” means including two or more algorithms, and the like.

In this specification and claims, reference is made to a number of terms that are defined to have the following meanings.

"Chemometrics" relates to the application of mathematical, statistical and pattern recognition techniques in chemical analysis applications. This is described, for example, by Brown et al. (1990) Anal. Chem. See 62: 84-101. Chemistry is practiced here with the development and use of non-invasive diagnostic instruments using advanced signal processing and calibration techniques. Signal processing is used to improve the accessibility of the physically important information of the analysis signal. Examples of signal processing techniques include Fourier transforms, first and second derivatives, and digital or adaptive filtering.

In the context of chemical metric, "calibration" refers to the process of relating measurement data to chemical concentrations for quantification. In particular, statistical calibration using chemimetric methods can be used to extract specific information from a complex set of data. Such calibration methods include linear regression, multi-linear regression, partial linear regression, and principal component analysis. In another application, calibration can be performed using simulated neural networks, general algorithms, and rotational principal component analysis.

Instruments that detect information about one or more components in a complex chemical matrix must rely on analytical algorithms (such as those derived using chemical metric methods) to present information specific to one or more chemical components. Chemmetric techniques can be used to compare unknowns to calibrated standards and databases and to extract features from unknown samples that can be used as information in statistical and mathematical models to provide advanced forms of cluster analysis.

"Principal Component Analysis" (PCA) is a method of data reduction that can be performed when applying chemimetric techniques to spectrophotometric measurements of chemical analytes in complex matrices. PCA is used to reduce the magnitude of many closely related variables while retaining information that distinguishes one component from another. This reduction uses eigenvector transformations that transform the original closely related set of variables (e.g., the absorption spectrum) into a substantially smaller set of uncorrelated principal components (PC) variables representing most of the information in the original set. Is executed. The new set of variables is arranged so that the first retains most of the changes present in all of the original variables. See, eg, Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (1986). More specifically, each PC is a linear combination of all original measurement variables. The first is the vector in the direction of the largest dispersion of the observation variables, the next PC represents the largest change in the measurement data and is chosen to be orthogonal to the precomputed PC. Thus, PCs are organized in descending order of importance.

The term “weighting constant” includes any constant obtained from the wavelength coefficients of partial least squares regression and / or principal component regression, or any statistical calibration that can be used to calculate values for unknown samples (such as analyte concentrations). do. A "wavelength weighter" is an embodiment of weighting constants used in the construction of optical filter means capable of emphasizing wavelength-specific information from spectral data. The wavelength-specific information can be used to measure certain values (eg, analyte concentrations) related to the sample to be analyzed. Wavelength weighting factors are specific filter densities (eg, neutral or wavelength-specific), filter thickness, etc. These parameters were measured using the statistical calibration technique described above.

Optical filters embodying wavelength weighting factors can be used to selectively highlight wavelengths that have a high correlation with the selected analyte concentration. "High correlation" or "root correlation" refers to the quantitative association between an absorption spectrum at a particular wavelength and a particular analyte concentration, with two variables having a correlation coefficient (r) of at least 0.9.

"Neutral concentration filter" refers to standard light filter means having a flat absorption spectrum. Neutral concentration filters can be used in conjunction with the filter system's correlation filter to provide weighting factors to attenuate absorbance due to the analyte at the selected wavelength and also improve the accuracy of the correlation provided by the system. The neutral concentration filter may have an absorption spectrum sufficient to equally attenuate radiation at all wavelengths within the range of interest.

As used herein, "aqueous medium" includes any compound that includes moisture. Generally, the aqueous medium contains water as the main component, ie at least about 50 vol. Moisture in an amount of% is present. Such aqueous media include, for example, mammalian tissue.

The term “blood analyte” refers to a blood component that absorbs in the near-IR range, the measurement of which is useful for the evaluation of patient surveillance or health care.

As used herein, the term “short wavelength infrared” or “near-IR” ranges from about 660 nm to 3500 nm, but typically ranges from about 1050 to 2850 nm, more typically from about 1100 to about 2500 nm. Contains radiation in the spectrum that is in the range of.

The term “mid-infrared” or “mid-IR” includes radiation in the spectrum ranging from about 3501 nm to about 6000 nm.

The term “background absorption” relates to the light absorption of the entire or base level of the aqueous sample to be analyzed, wherein the absorption of the selected component deviates from one or more characteristic wavelengths which mostly indicate the concentration of the selected component. When the level of background absorption is high relative to the characteristic absorption of the selected component, such as a composite aqueous medium in which many interference components are found, an accurate measurement of the gentle change in size in the absorption at the characteristic wavelength of the component of interest is here. It is necessary to apply the chemimetric techniques described in. In particular, this is the case when the total concentration of the components of interest is low compared to aqueous media, for example in the measurement of blood analytes.

Common way

A spectrophotometer method is provided for measuring the concentration of analyte in a liquid sample using near-IR radiation. In contrast to the prior art, the method uses all the spectral information contained in the near-IR region to obtain a set of measurements that can be used to measure the analyte concentration with a high degree of accuracy.

The method comprises the steps of: (1) selecting several individual, non-overlapping regions of wavelength from the near infrared range, generally over 1100 to 3000 nm, or the near infrared range, and generally the mid-infrared range over 3501 to 5000 nm, each of said Region defines a spectral range, (2) irradiating a sample using infrared light comprising a selected spectral range to obtain attenuated spectral modified radiation, and (3) obtaining within each selected spectral range Collecting and measuring the intensity of spectral attenuated radiation at one or more wavelengths, and (4) correlating the measurements to obtain a value representative of the analyte concentration.

Spectral information obtained using this method can be combined with mathematical modifications to reach accurate analyte concentration values, for example standard statistical techniques such as partial least squares (PLS) analysis, or principal component regression (PCR) analysis. Can be used to correlate radiation absorbance at a particular wavelength to the analyte structure and concentration. PLS techniques are described, for example, in Geladi et al. (1986) Analytica Chimica Acta 185: 1-17. For a description of the PCR technique, Jolliffe, L.T., Principal Component Analysis, Sprinter-Verlag, New York (1986) can be referred to.

Thus, in measuring blood analyte concentrations from body tissue specimens, one method involves the selection of three non-overlapping regions of wavelength in the near infrared, in the range of approximately 1100 to 3500 nm. Preferably, but not necessarily, the first region is in the range of 1100 to 1350 nm, the second region is in the range of 1430 to 1450 nm or 1930 to 1959 nm, and the third region is in the range of 2000 to 2500 nm. Each region defines a "spectrum range." The first region contains wavelengths in which proteins and other cellular components exhibit major spectral activity, the second region is governed by the absorption spectrum of moisture, and the third region contains wavelengths in which organic analyte molecules exhibit significant spectral activity. Include.

These components also contribute to the absorption spectrum of that region, not the dominant species. Thus, the spectral attenuated radiation obtained from each region contains a large amount of closely related information that must be attenuated using statistical methods to obtain analyte-specific information.

The invention also relates to the use of signal processing to improve the accessibility of physically important information of the analysis signal. Thus, the intensity value of the signal obtained at a particular wavelength can be processed to reduce the effects of device noise. The processed signal is then subjected to diversification analysis using known statistical techniques.

The PCA method of data reduction is one preferred method used in the practice of the present invention to reduce the magnitude of a number of closely related variables while retaining information that distinguishes one component from another. Data reduction is performed using eigenvector transformations that transform the original closely related variable set into a substantially smaller set of uncorrelated principal components (PC) variables that represent most of the information in the original set. The new set of variables is arranged so that the first retains most of the changes that exist in the original set.

The principal component vector is transformed by orthogonal rotation with respect to the average value of the absorbance to obtain both the known wavelength and the relative value of the absorbance at that wavelength contributing to the analyte. A system for measuring the concentration of an analyte by performing such an analysis on information obtained from each of the three spectral regions, using a subtractive method that cross-correlates the principal component vectors via a linear algorithm and removes the influence of the interfering analyte. A value that can be used for the algorithm is obtained.

Diversification techniques are used to provide a model that relates the radiation intensity at a particular wavelength in each spectral region to the analyte concentration in a particular sample matrix, eg, body tissue. The model is constructed using two sets of exemplary measurements obtained simultaneously, wherein the first set of measurements, " prediction set, " includes spectral data, for example radiation intensity at a selected wavelength, and a second set of measurements, “Calibration Set” includes highly accurate analyte concentrations measured using invasive sampling techniques. The procedure is run across a range of analyte concentrations to provide calibration and prediction data sets.

Measurements obtained in both calibration and prediction sets are subjected to diversification analysis to provide an initial model, such as by the use of an industry diversified model development software program, the initial model being applied to the predictive data and obtained by invasive techniques. Induce analyte concentration values that can be compared to values. By performing the above steps repeatedly, an improved mathematical model is developed that can be used to establish a system algorithm for use in analyzing the data obtained by the method of the present invention.

In practical applications of the present invention, non-analyte characteristic information from various non-overlapping spectral regions can be used, for example, to normalize each spectral scan, subtract background and baseline interference, It can be used to provide signal values used to detect inaccurate measurements.

Measurements taken in the spectral range over about 1320-1340 nm provide a highly reflective and non-attenuated signal since there are no major absorption bands present in the area when measuring blood analyte concentrations in body tissue samples. By collecting and measuring the intensity of irradiation in that range, a value is obtained that can be used to evaluate the actual intensity of the near-IR light used to irradiate the specimen. The value can be used to normalize each individual scan and correct for variations in light source intensity that may affect the accuracy of the analyte concentration values obtained using the method of the present invention.

In addition, measurements taken in the spectral range spanning about 1430-1450 nm are substantially anti-reflective, highly attenuated signals as a result of two predominant absorption peaks occurring at about 1440 and 1935 nm in the near-IR absorption spectrum for moisture. To provide. By collecting and measuring the intensity of the irradiation in one or both of these ranges, a value is obtained that can be used to evaluate the intensity of near-IR light that is not absorbed entirely by the irradiated sample. The value can be used to subtract background or base-line information from analyte-specific signals obtained in other areas and / or to provide internal criteria to detect inaccurate measurements. The value can be subtracted from each spectral measurement obtained using this method to correct the pedestal effect due to skin reflection and age-specific specular reflection.

Measurement of substantially non-attenuated signals obtained from a first region (e.g., a spectral region spanning about 1320-1340 nm) and a second region (e.g., a spectral region spanning about 1430-1450 nm and about 1930-1950 nm) The measurement of the highly attenuated signal obtained from can be used to compare the scattered reflected radiation with the specularly reflected radiation. If the signals in the two regions have relatively comparable values, most of the radiation used to irradiate the tissue sample will be reflected off the skin surface and will not penetrate the skin to interact with the blood analyte. This information can be used to identify inefficient measurements resulting from failure to obtain adequate instrument scans of tissue samples.

According to one aspect of the present invention, a method for measuring the concentration of an analyte in a sample provides a non-invasive measurement obtained with several individual, non-overlapping regions of wavelengths in the infrared region and an optical processing system particularly suitable for outdoor or indoor applications. Is provided using. The method generally comprises (1) several individual, non-overlapping regions of wavelengths preferably from the near infrared range over 1100 to 3000 nm, or from the near infrared range over 1100 to 3500 nm and the mid-infrared range over 3501 to 5000 nm. Selecting, (2) irradiating a sample using infrared light comprising spectral ranges selected to obtain spectral modified radiation, ie reflected radiation, and (3) removing a portion of the radiation from each non-overlapping region. Selectively filtering the spectrally modified radiation to isolate or highlight, (4) collecting and measuring the intensity of the selectively filtered radiation using a detector, and (5) optically filtering the given mathematical model Obtaining a value representative of the analyte concentration by use of The mathematical model may comprise a correlation algorithm obtained using the above-described chemical metric technique.

The method of the present invention can be performed using a number of spectrophotometer configurations. With reference to FIG. 1, one particular apparatus for measuring the concentration of an analyte in a liquid sample is generally indicated at 10. The apparatus includes a radiation source 12 that provides a plurality of individual, non-overlapping regions of wavelengths in the range of approximately 1100 to 5000 nm. Many suitable radiation sources are known in the art and are described herein, for example, incandescent light sources induced across interference filters, halogen light sources modulated by an associated chopper wheel, laser diode array, or high speed. Light emitting diode (LED) arrays can be used. In one particular apparatus, the radiation source 12 provides three separate regions of wavelengths, in particular the first region is a wavelength within 1100 to 1350 nm, the second region is a wavelength within an approximate range of 1930 to 1950 nm, The third region is a wavelength in the approximate range of 2000 to 3500 nm.

The apparatus 10 also includes sample interfering optical means 14 for firing incident radiation from a radiation source into contact with a sample medium 16 containing an analyte. After contact with the sample medium, spectral modified radiation from the sample as scattered reflected light is collected and transmitted to a multi-stage filter means, generally indicated at 18.

In various configurations, the sample interface optical means 14 is designed to enable a close interface between the medium 16 and the device 10, such as where firing is performed by placing the device in direct contact with the sample medium, thereby providing a radiation source. You can get close to the sample to be analyzed. After firing, the reflected radiation is collected using light active means, such as light converging means or beam refracting optics. Alternatively, the sample interface optical means 14 may comprise an optical fiber waveguide coupled to the device such that the remote device can be placed and operated. Another configuration is provided in which a single fiber optic bundle is used to transmit radiation to and from a medium. A photoelectrode placed at the end of a single bundle transmits near-IR radiation to the sample medium 14 and receives the spectrum-modified radiation returning back to the device 10 via a bundle. Sapphire or highly modified can be used as the optical element of the optical fiber waveguide because these materials have very good transmission properties in the near-IR spectral range.

Referring to FIG. 1, the reflected light from the sample 16 passes to the multistage filter means 18. In particular, the light passes to a first stage comprising variable filter means 20 which may be externally generated or have absorption characteristics which are adjusted in response to the signal generated by the device 10. The variable filter means generally comprise a screen filter, such as a neutral concentration filter having an absorption characteristic that is adjusted to variably attenuate the intensity of the radiation as indicated by an external signal or system command. The degree of attenuation provided by the variable filter means 20 is based on a predetermined factor selected to ensure that the radiation from the variable filter has a constant value regardless of the intensity of the pre-filtered radiation.

The attenuated radiation from the variable filter means 20 is the primary analyte filter having an optical property capable of selectively passing one or more wavelengths from each of the individual non-overlapping regions of the wavelengths emitted by the radiation source 12 ( 22). The wavelength passed by the primary analyte filter is chosen to correlate with the concentration of the analyte.

The second filter means 24 is arranged in the apparatus 10 associated with the primary analyte filter 22 such that the selectively passed wavelengths from the primary analyte filter interact with the second filter means. The second filter means has an absorption characteristic selected such that the intensity of each passed wavelength is attenuated by the second filter means. The attenuation provided by the second filter means can be determined by an independent set of weighting factors derived using, for example, chemimetric techniques.

In one particular configuration, weighting factors are determined using partial least squares or principal component regression of the original spectrum obtained from the sample comprising the analyte. The second filter means 24 can be constructed using a suitable substrate layer capable of transmitting radiation in the range of at least 1100 to 5000 nm. The substrate layer is generally coated with one or more metal and / or oxide layers commonly used in the art to provide a plurality of second filter densities. Such coatings may be applied to the substrate using emulsion or chemical vapor deposition (CVD) techniques that are well known in the art. In an alternative arrangement, the second filter means is a photographic mask having spectral lines of optical density proportional to the weighting function determined using rotational principal component analysis or least squares fractional techniques.

After attenuation by the second filter means, independent wavelengths are transferred to a detection means 26 such as one or more lead sulfide detectors, gallium arsenide detectors, and the like. In one particular device configuration, it is desirable to obtain specifications over the entire range of about 1100 to 5000 nm, and one or more lead selenide (PbSe) detectors may be used.

The detection means 26 detects the attenuated wavelengths from the second filter means and converts them into a signal that can be used in an analyte specific algorithm for measuring the analyte concentration. In particular, the signals obtained from the second detection means can be easily converted to digital signals using an analog / digital converter. The digitized information can be readily used for input to a microprocessor or other electronic memory means, which is used to provide analyte concentrations that can be displayed on a display device or recorded on an output recorder.

In an alternative arrangement, the device 10 may comprise a diffraction grating system and a linear detector instead of the multistage filter means 18. Reflected light from the sample 16 can be passed from there into a diffraction grating system configured to selectively pass discrete wavelengths, which in particular correlate with the concentration of the analyte. The passed wavelengths are then transferred to a linear detector array, such as a PbS based linear detector array. In certain applications for obtaining measurements over the full range of about 1100 to 5000 nm, PbSe based linear detectors may be used. PbSe linear arrays can be obtained, for example, under the product name MULTIPLEXIR ^™ (available from Grabyby Infrared, Orlando, Fla.).

As described above, the linear detector array collects and measures the wavelengths passed by the diffraction grating system to provide signals that can be used in an analyte specific algorithm for measuring analyte concentration.

Apparatus 10 may be used to obtain measurements of analyte concentrations in various synthetic media, such as aqueous media having synthetic spectral backgrounds. In one application, the device can be used to measure concentrations of blood analytes, but not limited to, organic blood non-analytes such as glucose, urea (BUN), lipids, bilirubin, and alcohols. The blood analyte can be present in a sample match (eg, a blood sample) in a bit or the device can be used to measure the blood analyte in the tissue. However, the device 10 is particularly suitable for the application of, for example, the measurement of blood alcohol or for the monitoring of home health, for example blood glucose measurement.

Referring to FIG. 2, another device for measuring the concentration of analyte in a sample is indicated by 50. The apparatus includes a radiation source 52 providing a plurality of individual, non-overlapping regions of wavelengths in the range of approximately 1100 to 5000 nm. The apparatus 50 also includes sample interface optical means 54 for emitting incident radiation from a radiation source to a contact with a sample medium 56 comprising an analyte. After contact with the sample medium, spectral modified radiation from the sample as scattered reflected light is collected and transmitted to a filter means 58 configured to pass light of certain wavelengths.

In operation, incident radiation is emitted from the radiation source 52 through the sample interface optical means to the sample medium, which sample interface optical means can be designed to enable the proximity interface of the device when a particular sample medium is analyzed. have. After firing, the reflected radiation is collected using optically active means such as light converging means (ie lenses) or beam deflection optics. The sample interface optical means 54 may comprise an optical fiber waveguide coupled to the device 50 to enable remote device displacement and operation. As mentioned above, one alternative system uses a single fiber optic bundle to deliver radiation to and from the medium.

The reflected radiation is directed to the filter means 58 comprising a plurality of discrete filter elements represented by λ ₁ , λ ₂ , λ ₃ ,..., Λ _n . Filter means 58 may be used for non-analyte specific information, information about the measurement background, and correction for mechanical changes or interference effects. The selected wavelengths from the filter means are generally detected by the arrangement of detectors 60 with a plurality of discrete detector means, denoted D ₁ , D ₂ , D ₃ ,..., D _n . The detectors are detected by a single, discrete detector with each selected wavelength range coming from the filter means. Suitable detector configurations are known in the art and may include, for example, an array of PbS or PbSe detectors. Each detector converts the detected radiation into an electrical signal that can be used to obtain a value representative of the analyte concentration.

The signals obtained from the detectors are easily converted into digital signals, for example digital signals indicative of the intensity of the detected wavelengths, using an analog / digital converter. This digitalized information can then be input to the microprocessor for further processing (eg, used in system algorithms), or the information can be displayed via electronic display means. Analog signals obtained from each discrete detector are passed to an analog / digital (A / D) converter for conversion to digital form. Analog signals can be pre-amplified prior to conversion using techniques known in the art. The digital information from the A / D converter is then easily entered into the microprocessor to calculate the analyte concentration using a system algorithm specific to the analyte. The microprocessor calculates the analyte concentration by using a chemimetric algorithm on the detected signals. Non-analyte specific algorithms can be determined using iterative calibration and statistical modeling techniques, such as the chemimetric methods described above.

In practical applications of the present invention, the filter means 58 may be configured to include at least one discrete filter element having an absorption characteristic that can improve the correlation of the wavelength passed with the concentration of the analyte. In particular, the filter means may comprise one or more filter elements which attenuate the intensity of the wavelength passed as determined by an independent set of weighting factors derived, for example using chemimetric techniques. These weighting factors can be derived using partial least squares or principal component regression of the original spectrum obtained from the sample comprising the analyte.

In another alternative arrangement, the filter means 58 comprises a two stage filter, the first stage comprising a plurality of portions configured to selectively pass a population of wavelength ranges selected from attenuated radiation reflected from the sample. Include. The selectively passed wavelengths include analyte specific information, information about the measurement background, and information that can be used to correct for mechanical change or interference effects. The second end of the filter is disposed immediately adjacent to the first end and serves to attenuate the intensity of each of the passed wavelengths from the first end. The second stage of the two stage filter may be a neutral concentration filter having a flattened absorption spectrum sufficient to evenly attenuate the intensity of each of the passed wavelengths from the first stage of the filter.

The device 50 may be used to identify the concentration of one or more analytes of interest present in various synthetic media, such as aqueous media having synthetic spectral backgrounds. In particular, the device can be used to measure the concentration of blood analytes, especially but not limited to organic blood analytes such as glucose, urea (BUN), lipids, bilirubin, and alcohols. As noted above, the concentration of blood analyte can be processed using the sample as a bit, or the analysis can be performed using a near infrared scan of the tissue, such as a reflection measurement obtained from a forearm tissue scan.

When the device 50 is used to obtain a blood analyte measurement from a tissue source, incident radiation emitted from the radiation source 52 via the sample interface optical means 54 causes the skin surface of the tissue, such as the forearm of the subject, to invade. do. The sample interface optical means induces radiation at a constant angle towards the tissue such that the radiation is absorbed by the tissue material near the surface and reflected as scattered radiation. Incident radiation is spectrally modified as a result of infrared absorption by blood and tissue components. Portions of incident near infrared radiation are absorbed, dispersed, diffused, and reflected from blood components present in the tissue source. Each of these spectral modified radiation contains specific information about the optically activated blood component.

In measuring blood glucose levels using the device 50, vibrational motion of blood glucose molecules is detected and measured using scatter-reflecting near infrared radiation. Vibration motions include both rotational and translational motions of glucose molecules, including overtone vibrations and combined vibrations. Of these operations, overtone vibration is dominant and occurs in the range of approximately 1670-1690 nm. Glucose combination vibration bands occur in the range of approximately 2120 to 2280 nm. Glucose does not have significant optical activity within the near infrared range of approximately 1320-1340 nm.

Thus, the device 50 comprises a filter means 58 having four separate parts, wherein the first part is configured to pass radiation reflected from a region of wavelengths in the range of approximately 1300 to 1360 nm, and The two portions are configured to pass radiation reflected from a region of wavelengths in the range of approximately 1430-1450 nm or in the range of approximately 1930-1950 nm, and the third portion reflects from the region of wavelengths in the range of approximately 1670-1690 nm. And pass through the reflected radiation from the region of wavelengths in the range of approximately 2120 to 2280 nm.

The intensity of the wavelengths passed by the third and fourth portions of the filter means comprises the analyte specific information. As noted above, the third and fourth filter portions include weighting factors that enhance the correlation of the radiation passed with the concentration of glucose present in the tissue sample. The information obtained from the first portion of the filter can be used to predict the background spectral contribution at each measurement and thus can be used to correct or normalize the measurements obtained from the third and fourth filter portions. The signals obtained from the second filter portion (water absorption information) can be used as an internal test to identify when an invalid measurement, e.g., to obtain an appropriate mechanical scan of a tissue sample, or the information is from the third and fourth filter portions. It can be used to compensate for temperature changes in the measurements obtained.

Although the present invention has been described with respect to specific preferred embodiments, it is to be understood that the above description as well as the following examples are intended to be illustrative and not limiting the scope of the invention. It will be apparent to those skilled in the art that other features, advantages and modifications within the scope of the invention are included in the invention.

Example

Noninvasive glucose measurements were obtained using the method of the present invention. In particular, reflected light measurements were performed in the near-IR region of about 1100 nm to 3500 nm. Spectral scans were collected from volunteer forearm subjects using a tungsten-mercury (W-Hg) radiation source, lead sulfide (PbS) detector, and an instrument with a scan rate of nm / 0.4 sec.

Many specific spectral ranges have been distinguished as including information that can be used to determine glucose concentration from forearm tissue scans. Specialized regions were determined from studies of in vivo glucose tolerances performed in concert with non-invasive determination of blood glucose concentrations in vitro. In particular, the time-dependent scan obtained during the study of tolerances in vivo is shown in FIG. 3. As can be seen, a significant change in the reflection intensity difference over the range of about 2120 to 2180 nm was recorded during the study. These changes increased directly in relation to the increase in blood glucose levels during the tolerance test, indicating that the glucose specific information included a range of 2120 to 2180 nm.

Once specific spectral ranges were identified, noninvasive glucose measurements were obtained using information from four unique spectral ranges. The first spectral range included radiation occurring at about 1320-1340 nm. This range provides a very large reflected signal and there is no major glucose absorption band in this range. The information obtained from the first spectral range can be used to normalize each individual scan to correct for variations in the radiation source and vary due to mechanical perturbation.

The second spectral range included radiation occurring at about 1440 to 1460 nm, or about 1940 to 1960 nm. These ranges provide a substantially antireflective signal due to a large band of adsorption water that attenuates scattered reflected radiation. The information obtained from these ranges can be used for background and base line subtraction from other measurements. This measurement allows pedestal adjustment to account for variations due to specular signal values and can be used to detect improper measurements.

The third range included radiation occurring at about 1670-1690 nm. This range provides the analyte-specific information due to the glucose oscillating harmonics.

The fourth range included radiation occurring at about 2120 to 2280 nm. This range provides the analyte-specific information due to the glucose combination oscillation band.

The signal obtained from the first range was used to normalize the signal in the other region. This process serves to eliminate problems associated with changes in the light source and to provide internal criteria when repeated with each spectral scan. Thus, measurement changes due to differences in optical interfaces, eg patient placement, have been substantially reduced.

Background information was removed by subtracting the signal obtained in the second range from the signal obtained in the third and fourth analyte-specific ranges. In this way, the pedestal effect produced by the skin and age and the specular reflection changes with age was corrected.

Signals normalized from the third and fourth ranges and the baseline corrected were subjected to analytical chemimetric analysis. 4 shows a normalized difference between signals in the second and third ranges.

As can be seen from the results shown in FIG. 4, the signal difference between the two ranges is increased by increasing the blood glucose level.

Claims (28)

A method of measuring the concentration of an organic blood analyte in a body tissue sample, (a) irradiating the sample with incident radiation in a wavelength region between 1100 and 5000 nanometers in a beam path; (b) collecting the reflected radiation from the sample: (c) receiving reflected radiation from the sample with detection means disposed in the beam path; (d) converting the detected reflected radiation into a signal; (e) analyzing the signal to determine the concentration of the analyte; And (f) providing criteria for detecting inaccurate measurements; And the body tissue sample, particularly for water, in the near-IR absorption spectrum, for at least one of identifying invalid measurements resulting from failure to obtain an appropriate mechanical scan of the tissue sample. Measuring the intensity of radiation from the How to include. The method of claim 1, The detection means, Lead selenide (PbSe) linear detector arrays; Lead sulfide (PbS) linear detector arrays; At least one detector made from any of PbSe, PbS, and Gallium Arsenide (GaAs) How to include one of the. The method of claim 1, Wherein said infrared spectrum comprises a spectral region of wavelengths in the range of 1100 to 1350 nm, an additional spectral region of wavelengths in the range of 2000 to 3500 nm, and another further spectral region of wavelengths between these spectral regions. The method of claim 1, Said organic blood analyte is selected from the group consisting of glucose, urea (BUN), lipids, bilirubin, and ethyl alcohol. The method of claim 4, wherein Said blood analyte is glucose. A method for identifying invalid measurements in a method of measuring the concentration of an organic blood analyte in a body tissue sample, Irradiating the sample with incident radiation in a wavelength region between 1100 and 5000 nanometers; Collecting the reflected radiation from the sample; Detecting reflected radiation from the sample; Converting the detected reflected radiation into a signal; And The intensity of specular reflection radiation by measuring the intensity of the reflected radiation coming from the sample, represented by the signal, at wavelength bands that absorb the incident radiation and attenuate the diffusely reflected radiation To measure How to include. The method of claim 1, The near infrared absorption spectrum comprises spectral regions in the range of 1430-1450 nm and 1930-1950 nm. The method of claim 7, wherein The near infrared absorption spectrum for the moisture includes absorption peaks at 1440 nm and 1935 nm. The method of claim 1, The intensity of the radiation from the body tissue sample includes substantially non-attenuated signals obtained from the spectral region in the range 1320-1340 nm and includes heavily attenuated signals obtained from the spectral regions in the range 1430-1450 nm and 1930-1950 nm. Way. The method of claim 6, The wavelength bands comprise moisture bands. The method of claim 6, Wherein the wavelength bands include any of 1440-1460 nanometers and 1940-1980 nanometers. The method of claim 6, Comparing specular reflection measurements with signal measurements from a wavelength band where the scattered radiation is substantially not attenuated. More, Substantially comparable values for both measurements indicate an invalid measurement. An apparatus for measuring the concentration of an organic blood analyte in a human tissue sample, (a) means for irradiating said sample with incident radiation comprising a plurality of individual non-overlapping spectral regions within an infrared spectrum; (b) means for collecting the reflected radiation from the sample and directing the reflected radiation to a beam path; (c) adjustable filter means disposed in the beam path, the variable filter means attenuating the intensity of the radiation in the beam path; (d) principal analyte filter means capable of receiving attenuated radiation from said variable filter means and selectively passing discrete wavelengths therefrom, said discrete wavelengths being specific to the concentration of said analyte; Correlated with-; (e) second filter means capable of receiving said discrete wavelengths from said primary analyte filter means and attenuating the intensity of said wavelengths; (f) detection means for receiving the attenuated wavelengths from the second filter means; And (g) means for converting the detected wavelengths into a signal representing the intensity of the wavelengths Device comprising a. The method of claim 13, Said variable filter means comprising a neutral density filter used in cooperation with the correlation filters in the filter system. The method of claim 13, And said second filter means comprises a neutral concentration filter used in coordination with the correlation filters in the filter system. The method of claim 15, The attenuation provided by the second filter means is set using weighting factors. The method of claim 16, Wherein the weighting factors are derived using chemometrics techniques. The method of claim 17, Wherein the weighting factors are derived using rotated principal components analysis of the absorption spectrum of the analyte. The method of claim 13, And the detector means comprises a lead selenide detector. An apparatus for measuring the concentration of an organic blood analyte in a body tissue sample, (a) means for irradiating said sample with incident radiation comprising a plurality of individual non-overlapping spectral regions within an infrared spectrum; (b) means for collecting the reflected radiation from the sample and directing the reflected radiation to a beam path; (c) filter means disposed in the beam path and including a plurality of sections configured to selectively pass at least one wavelength from the reflected radiation from the sample; (d) a plurality of detectors arranged such that each wavelength from said filter means is detected by a separate detector; And (e) means for converting the detected wavelengths into a signal representing the intensity of the wavelengths Device comprising a. The method of claim 20, The filter means comprises a first stage comprising a plurality of sections configured to selectively pass at least one wavelength from the reflected radiation from the sample and disposed adjacent to the first stage; And a two-stage filter having a second stage capable of attenuating each intensity of a selectively passed wavelength from said first stage of said filter means. The method of claim 21, And said second stage of said two stage filter is a neutral concentration filter. The method of claim 20, The filter means comprises a plurality of individual filter elements. The method of claim 23, Wherein the at least one individual filter element comprises an absorption characteristic selected to provide an enhanced correlation of the wavelength passed and the concentration of the analyte. The method of claim 20, And the plurality of detectors comprises lead selenide (PbSe) detectors. The method of claim 20, The filter means is configured to pass at least one wavelength from a first spectral analysis region of wavelengths in the range of 1300 to 1360 nm, at least one from a second spectral analysis region of wavelengths in the range of 1670 to 1690 nm. A second section configured to pass a wavelength, a third section configured to pass at least one wavelength from a third spectral analysis region of wavelengths in a range of 1930 to 1950 nm, and a fourth of wavelengths in a range of 2120 to 2280 nm And a fourth section configured to pass at least one wavelength from the spectral analysis region. An apparatus for measuring the concentration of an organic blood analyte in a human tissue sample, (a) means for irradiating said sample with incident radiation comprising a plurality of individual non-overlapping spectral regions within an infrared spectrum; (b) means for collecting reflected radiation from said sample and directing the reflected radiation to a beam path; (c) diffraction grating means disposed in the beam path and capable of receiving reflected radiation from the sample and selectively passing discrete wavelengths therefrom, wherein the discrete wavelengths specifically correlate with the concentration of the analyte; (d) a linear detector array for receiving the passed wavelengths from the diffraction grating means; And (g) means for converting the detected wavelengths into a signal representing the intensity of the wavelengths Device comprising a. The method of claim 27, And the linear detector array comprises a lead selenide (PbSe) linear detector array.